A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel

Armstrong, Nigel; Olaye, Andrew; Noake, Caro; Pang, Francis

doi:10.1186/s13023-023-02814-2

Orphanet Journal of Rare Diseases

Table 4 Progressive disease by treatment

From: A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel

Treatment	MLD type	Symptom status	Time point	Outcome definition	n/N (%)	Source
Atidarsagene	LI	Mixed	NR/unclear	No. progressed to death	0/16 (0%)	Fumagalli et al. [13]
Atidarsagene	EJ	Mixed	8 and 15 months post-treatment	No. progressed to death	2/13 (15%)	Fumagalli et al. [13]
HSCT	NR/unclear	Pre-symp	Post-HSCT	No. remaining asymptomatic	NR/8 (NR%)^c	Bohringer [19]—NR*
	NR/unclear	Symptomatic	Post-HSCT	No. with progression resulting in neurological disease	NR/8 (NR%)^d	Bohringer [19]—NR*
	LI to LJ^j	Mixed	Median 5.1 years (range 2.4–14.7)⁺	No. with significant disease progression	10/27 (37%)	Martin [23]—R
	LI to J	Mixed	1 year	No. progressed to death	2/7 (28.6)^h	Van Rappard [17]—R
	LI	Mixed	Median 5.1 years (range 2.4–14.7)⁺	No. with significant disease progression	6/10 (60%)	Martin [23]—R
	LI	Mixed	1 year	No. progressed to death	1/2 (50%)^h	Van Rappard [17]—R
	EJ	Mixed	NR/unclear	No. with further progression of disease	3/3 (100%)^a	Bley [18]—R*
	J	Mixed	Median 7.5 years (range: 3.0–19.7)⁺	No. long-term surviving patients with SD	11/20 (55%)	Groeschel [16]—R*
	J	Mixed	10 years⁺	No. long-term surviving patients with SD	12/20 (60%)	Groeschel [16]—R*
	J	Mixed	10 years⁺	No. disease progression resulting in a low level of GMF or loss of language	8/20 (40%)	Groeschel [16]—R*
	J	Mixed	Median 7.5 years (range 3.0–19.7)⁺	No. progressed to death	2/24 (8.3%)	Groeschel [16]—R*
	J	Mixed	1 year	No. progressed to death	1/5 (20%)^h	Van Rappard [17]—R
	J	Mixed	Latest follow-up	No. progressed to death	2/16 (12.5%)ⁱ	Boucher [21]—R
	J	Mixed	Median 7.5 years (range 3.0–19.7)⁺	No. long-term surviving patients with disease progression	9/20 (20%)	Groeschel [16]—R*
	J	Mixed	Median 5.1 years (range 2.4–14.7)⁺	No. with significant disease progression	4/17 (23.5%)	Martin [23]—R
	LJ^j	Mixed	Unclear	No. with further progression of disease	0/2 (0%)^b	Bley [18]—R*
Standard care	NR/unclear	NR/unclear	Mean 4.8 years (3.5–6 years) after first symptom	No. progressed to death	3/11 (27.2%)^e	Singh [20]—R^g
	NR/unclear	NR/unclear	Approximately 2 years	No. with disease progression resulting in developmental regression	9/11 (81.8%)^f	Singh [20]—R^g
	NR/unclear	NR/unclear	Approximately 5 years	No. with disease progression resulting in developmental regression	11/11 (100%)^f	Singh [20]—R^g
	J	Mixed	10 years**	No. long-term surviving patients with SD	13/41 (31.7%)	Groeschel [16]—R*
	J	Mixed	10 years**	No. disease progression resulting in a low level of GMF or loss of language	28/41 (68%)	Groeschel [16]—R*
	J	Mixed	Median 7.5 years (range 3.0–19.7)	No. progressed to death	11/41 (26.8%)	Groeschel [16]—R*

Mixed refers to populations with a mixture of pre-symptomatic and symptomatic patients
GMF gross motor function, I infantile MLD, J juvenile MLD, EJ early juvenile MLD, LJ late juvenile MLD, HSCT haemopoietic stem cell transplantation, MLD metachromatic leukodystrophy, mth month, No. number of patients, n number alive, N total number analysed, NR not reported, P prospective study, Pre-symp pre-symptomatic, R retrospective study, SD stable disease, yr year
*Indicates that there is a possibility of overlap with populations reported in other studies based in German study centres and/or using the LEUKONET database
Time point is reported as described by the author(s), where possible the baseline from which time is measured is stated: ⁺ After treatment (NR); ** After disease onset
^an = 2 received HSCT early during the pre-symptomatic phase, and n = 1 had developed gait disturbance around the time of HSCT. All tested normal in psychodevelopmental tests
^bOne of the two patients had cognitive and motor deficits at the time of HSCT, and the other was symptom-free and remained so for past 10 years
^cPatients asymptomatic prior to HSCT stayed asymptomatic
^dPatients who presented with neurological symptoms showed various degrees of progression
^e3 children died, and 8 children were alive at the time of the study analysis
^fMost children presented with developmental regression at 2 years of age, but n = 2 manifested with symptoms after 5 years of age
^gCurrent age of children at the time of analysis was mean of 10.1 years (range 4.9–20.6); children died and 8 children were alive at the time of the study analysis; mean time in years after first symptom to death was 4.8 years (range 3.5–6)
^hAll were symptomatic patients
ⁱAmong 16J-MLD patients in our cohort who did not die from transplant-related causes, 2 died from progressive MLD at 8 years and 5 years following initial disease onset
^jLJ disease is no longer relevant to the indication for Atidarsagene treatment

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ISSN: 1750-1172

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